1. Treatment for Restless Legs Syndrome
Prepared for:
Agency for Healthcare Research and Quality (AHRQ)
Treatment for Restless Legs Syndrome
This slide set is based on a comparative effectiveness review (CER), Treatment for Restless Legs Syndrome, Comparative Effectiveness Review No. 86, which was developed by the Minnesota Evidence-based Practice Center, Minneapolis, MN, for the Agency for Healthcare Research and Quality under Contract No I and is available online at
CERs are comprehensive systematic reviews of the literature that usually compare two or more types of interventions with usual care for the same disease. For this CER, the existing body of evidence on the relative benefits and adverse effects of currently available therapies for restless legs syndrome (RLS) was reviewed. The literature included in this review was identified in searches for studies in the MEDLINE® (via OVID), EMBASE®, and Natural Standards databases using relevant search terms and covering the period through June Studies in adults and children with RLS were included. The review did not include studies that lasted less than 4 weeks or that evaluated pharmacologic treatments not approved for any indication in the United States. Outcomes assessed included validated RLS symptom or quality-of-life scale scores, clinician and patient global impact scale scores, or measures of sleep quality.
Reference
Wilt TJ, MacDonald R, Ouellette J, et al. Treatment for Restless Legs Syndrome. Evidence Report No. 86 (Prepared by the Minnesota Evidence-based Practice Center under Contract No I). AHRQ Publication No. 12(13)-EHC147-EF. Rockville, MD: Agency for Healthcare Research and Quality; November Available at

2. Outline of Material
Introduction to restless legs syndrome (RLS) and the various therapies available for its treatment
Systematic review methods
The clinical questions addressed by the comparative effectiveness review
Results of studies and evidence-based conclusions about the relative benefits and adverse effects of currently available treatments for RLS
Gaps in knowledge and future research needs
What to discuss with patients and their caregivers
Outline of Material
The material in this presentation covers the results and conclusions from a systematic comparative effectiveness review entitled Treatment for Restless Legs Syndrome. It begins with an introduction to restless legs syndrome (RLS) and the types of therapies currently available for its treatment. It also covers methods used to plan and execute the systematic review, clinically important questions the review sought to answer, results of the review, evidence-based conclusions about relative effectiveness and safety of the currently available therapies for RLS, gaps in knowledge, and the future research needs uncovered by the systematic review.
Reference
Wilt TJ, MacDonald R, Ouellette J, et al. Treatment for Restless Legs Syndrome. Evidence Report No. 86 (Prepared by the Minnesota Evidence-based Practice Center under Contract No I). AHRQ Publication No. 12(13)-EHC147-EF. Rockville, MD: Agency for Healthcare Research and Quality; November Available at
Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86.
Available at

3. Background: What Is Restless Legs Syndrome?
Restless legs syndrome* (RLS) is a neurological disorder defined and diagnosed based solely on clinical criteria.
RLS diagnosis requires that the following four essential criteria be met:
There is an urge to move the legs that is usually accompanied by uncomfortable or unpleasant sensations in the legs.
Unpleasant sensations or the urge to move begin or worsen during periods of rest or inactivity such as lying or sitting.
Unpleasant sensations or urge to move are partly or totally relieved by movement such as walking, bending, stretching, et cetera, at least as long as the activity continues.
Unpleasant sensations or the urge to move are worse in the evening or at night than during the day or only occur in the evening or night.
* Also referred to as Willis-Ekbom disease
Background: What Is Restless Legs Syndrome?
Restless legs syndrome (RLS) is a neurological disorder that is characterized by unpleasant sensations in the legs and a distressing, irresistible urge to move them. RLS can result in reduced quality of life and interrupt sleep, leading to daytime fatigue.
The essential diagnostic criteria for RLS were established by the International Restless Legs Syndrome (IRLS) Study Group in 1995, were updated in 2003, and will be revised soon. A diagnosis of RLS requires that the following four criteria established by the IRLS Study Group be met:
There is an urge to move the legs that is usually accompanied by uncomfortable or unpleasant sensations in the legs.
Unpleasant sensations or the urge to move begin or worsen during periods of rest or inactivity such as lying or sitting.
Unpleasant sensations or the urge to move are partly or totally relieved by movement such as walking, bending, stretching, et cetera, at least as long as the activity continues.
Unpleasant sensations or the urge to move are worse in the evening or at night than during the day or only occur in the evening or night.
Additionally, these symptoms should not be solely accounted for by another condition such as leg cramps, positional discomfort, leg swelling, or arthritis.
References
Allen RP, Picchietti D, Hening WA, et al. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med Mar;4(2): PMID:
Trenkwalder C, Paulus W. Restless legs syndrome: pathophysiology, clinical presentation and management. Nat Rev Neurol Jun;6(6): PMID:
Wilt TJ, MacDonald R, Ouellette J, et al. Treatment for Restless Legs Syndrome. Evidence Report No. 86 (Prepared by the Minnesota Evidence-based Practice Center under Contract No I). AHRQ Publication No. 12(13)-EHC147-EF. Rockville, MD: Agency for Healthcare Research and Quality; November Available at
Allen RP, Picchietti D, Hening WA, et al. Sleep Med Mar;4(2): PMID:
Trenkwalder C, Paulus W. Nat Rev Neurol Jun;6(6): PMID:
Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86.
Available at

4. Background: Prevalence and Etiology of Restless Legs Syndrome
Prevalence estimates for restless legs syndrome (RLS) in the United States range from 1.5 to 7.4 percent in adults.
The variation reflects different approaches to diagnosing RLS and defining its frequency and severity.
The etiology of primary RLS is unknown, but the disorder also occurs secondary to other conditions such as iron deficiency, end-stage renal disease, and pregnancy.
Insufficient sleep and sleep disorders such as sleep apnea might exacerbate symptoms of RLS.
The pathophysiology of RLS has been suggested to be closely linked to abnormalities in the dopaminergic system and iron metabolism.
Background: Prevalence and Etiology of Restless Legs Syndrome
Prevalence estimates for restless legs syndrome (RLS) in the United States range from 1.5 to 7.4 percent in adults. The variation reflects different approaches to diagnosing RLS and defining its frequency and severity and the fact that many RLS questionnaires do not account for individuals who have conditions with similar symptoms.
The etiology of primary RLS is unknown, but the disorder also occurs secondary to other conditions such as iron deficiency, end-stage renal disease, and pregnancy. Insufficient sleep and sleep disorders such as sleep apnea might exacerbate symptoms of RLS.
A family history of RLS is common, and twin studies have shown heritability estimates of 54 to 83 percent. However, findings from genome-wide association studies have been inconsistent. When compared with primary RLS, secondary RLS is less common, often starts later in life, progresses more rapidly, and tends to resolve when the underlying condition is treated or resolved.
Although mechanistic relationships are not well established, the pathophysiology of RLS may be closely linked to abnormalities in the dopaminergic system and iron metabolism.
References
Allen RP, Picchietti D, Hening WA, et al. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Medicine Mar;4(2): PMID:
García-Borreguero D, Egatz R, Winkelmann J, et al. Epidemiology of restless legs syndrome: the current status. Sleep Med Rev Jun;10(3): PMID:
Trenkwalder C, Paulus W. Restless legs syndrome: pathophysiology, clinical presentation and management. Nature Rev Neurol Jun;6(6): PMID:
Wilt TJ, MacDonald R, Ouellette J, et al. Treatment for Restless Legs Syndrome. Evidence Report No. 86 (Prepared by the Minnesota Evidence-based Practice Center under Contract No I). AHRQ Publication No. 12(13)-EHC147-EF. Rockville, MD: Agency for Healthcare Research and Quality; November Available at
Allen RP, Picchietti D, Hening WA, et al. Sleep Med Mar;4(2): PMID:
García-Borreguero D, Egatz R, Winkelmann J, et al. Sleep Med Rev Jun;10(3): PMID:
Trenkwalder C, Paulus W. Nature Rev Neurol Jun;6(6): PMID:
Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86.
Available at

5. Background: Severity and Clinical Course of Restless Legs Syndrome
Restless legs syndrome (RLS) can be defined as mild, moderate, severe, or very severe based on the International RLS (IRLS) Rating Scale.
The IRLS is a 10-item scale with scores ranging from 0 (no symptoms) to 40.
A score of ≤10 is considered mild RLS, a score of 11–20 is considered moderate RLS, a score of 21–30 is considered severe RLS, and a score >30 is considered very severe RLS.
Mild RLS may cause minor annoyance.
Severe RLS can negatively affect work, social activities, and function. It can be a chronic progressive disorder that may require long-term treatment.
RLS-induced sleep deprivation and daytime fatigue are common reasons RLS patients seek treatment.
Background: Severity and Clinical Course of Restless Legs Syndrome
Restless legs syndrome (RLS) varies in symptom severity and frequency. RLS can be defined as mild, moderate, severe or very severe based on the IRLS Rating Scale. The IRLS is a 10-item scale with scores ranging from 0 (no symptoms) to 40. Scores ≤10 are considered mild RLS, scores of 11–20 are considered moderate RLS, scores of 21–30 are considered severe RLS, and scores >30 are considered very severe RLS.
Mild RLS may cause minor annoyance, but severe RLS can interfere with work, social activities, function, and emotional well-being. RLS-induced sleep disruption may lead to poor daytime functioning, anxiety, and depression. Severe RLS can be a chronic progressive disorder that may require long-term treatment.
Sleep deprivation and daytime fatigue are common reasons RLS patients seek treatment. If left untreated, severe and bothersome RLS can result in a greatly reduced quality of life.
References
Trenkwalder C, Paulus W. Restless legs syndrome: pathophysiology, clinical presentation and management. Nat Rev Neurol Jun;6(6): PMID:
Wilt TJ, MacDonald R, Ouellette J, et al. Treatment for Restless Legs Syndrome. Evidence Report No. 86 (Prepared by the Minnesota Evidence-based Practice Center under Contract No I). AHRQ Publication No. 12(13)-EHC147-EF. Rockville, MD: Agency for Healthcare Research and Quality; November Available at
Trenkwalder C, Paulus W. Nat Rev Neurol Jun;6(6): PMID:
Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86.
Available at

6. Background: Currently Available Treatment Options for Restless Legs Syndrome (1 of 2)
Treatment options for restless legs syndrome (RLS) include pharmacologic and nonpharmacologic strategies.
The major classes of pharmacologic treatments* include:
Dopaminergic agents
Anticonvulsant calcium channel (alpha-2-delta) ligands
Iron
Pharmacologic agents approved by the U.S. Food and Drug Administration (FDA) for treating moderate to severe RLS are:
Dopamine agonists: Pramipexole (Mirapex®), ropinirole (Requip®), and rotigotine patch (Neupro®)
Alpha-2-delta ligand: Gabapentin enacarbil (Horizant®)
*The authors of this review did not identify any eligible studies that tested sedative hypnotics and opioids in RLS patients. Sedative hypnotics and opioids are not approved by the FDA for treating RLS.
Background: Currently Available Treatment Options for Restless Legs Syndrome (1 of 2)
Treatment options (nonpharmacologic and pharmacologic) for restless legs syndrome (RLS) vary by patient age, comorbidities, preferences, and disease severity.
Pharmacologic treatment is generally reserved for patients with symptoms that are frequent (several times per week) and that cause moderate to very severe discomfort and bother. The major classes of drugs used are dopaminergic agents (including levodopa, ropinirole, pramipexole, and rotigotine), anticonvulsant alpha-2-delta calcium channel ligands (including gabapentin, gabapentin enacarbil, and pregabalin), sedative hypnotic agents (including clonazepam, temazepam, and oxazepam), opioids (including hydrocodone, codeine, tramadol, oxycodone or oxycodone XR, methadone, and morphine sulfate XR), and iron (several formulations). Of these, three dopamine agonists (pramipexole, ropinirole, and rotigotine) and one calcium channel (alpha-2-delta) ligand (gabapentin enacarbil) are approved by the U.S. Food and Drug Administration for the treating moderate to severe RLS.
References
Silber MH, Ehrenberg BL, Allen RP, et al; Medical Advisory Board of the Restless Legs Syndrome Foundation. An algorithm for the management of restless legs syndrome. Mayo Clin Proc Jul;79(7): PMID:
Wilt TJ, MacDonald R, Ouellette J, et al. Treatment for Restless Legs Syndrome. Evidence Report No. 86 (Prepared by the Minnesota Evidence-based Practice Center under Contract No I). AHRQ Publication No. 12(13)-EHC147-EF. Rockville, MD: Agency for Healthcare Research and Quality; November Available at
Silber MH, Ehrenberg BL, Allen RP, et al. Mayo Clin Proc Jul;79(7): PMID:
Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86.
Available at

7. Background: Currently Available Treatment Options for Restless Legs Syndrome (2 of 2)
Nonpharmacologic treatment approaches for restless legs syndrome (RLS) include:
Exercise
Avoiding RLS precipitants such as caffeine, alcohol, antidepressants, and antihistamines
Using counter stimuli to sensory symptoms such as hot or cold baths, limb massage, compression stockings, and counter-pulsation devices
Near-infrared light therapy
Herbal medicine
Acupuncture
Background: Currently Available Treatment Options for Restless Legs Syndrome (2 of 2)
Nonpharmacologic options for treating RLS include exercise; avoiding RLS precipitants (caffeine, alcohol, antidepressants, AND antihistamines); counter stimulus to sensory symptoms (hot or cold baths, limb massage, compression stockings, and counter-pulsation devices); near-infrared light therapy; herbal medicines; acupuncture; and cognitive behavioral therapy.
References
Silber MH, Ehrenberg BL, Allen RP, et al; Medical Advisory Board of the Restless Legs Syndrome Foundation. An algorithm for the management of restless legs syndrome. Mayo Clin Proc Jul;79(7): PMID:
Wilt TJ, MacDonald R, Ouellette J, et al. Treatment for Restless Legs Syndrome. Evidence Report No. 86 (Prepared by the Minnesota Evidence-based Practice Center under Contract No I). AHRQ Publication No. 12(13)-EHC147-EF. Rockville, MD: Agency for Healthcare Research and Quality; November Available at
Silber MH, Ehrenberg BL, Allen RP, et al. Mayo Clin Proc Jul;79(7): PMID:
Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86.
Available at

8. Background: Restless Legs Syndrome Treatment and Augmentation
Dopaminergic agents (dopamine agonists and levodopa) used in restless legs syndrome therapy can result in a complication called augmentation in the long term.
Augmentation is a drug-induced exacerbation of symptoms characterized by greater symptom intensity, onset earlier in the day, and shorter latency during inactivity.
Incidence of augmentation may vary with type of dopaminergic agent.
Augmentation is more likely to occur with levodopa than with dopamine agonists.
Augmentation is usually considered resolved when:
The medication triggering augmentation has been discontinued
The patient has been switched to
Background: Restless Legs Syndrome Treatment and Augmentation
Dopaminergic agents (dopamine agonists and levodopa), which are used to treat restless legs syndrome, can result in a complication called augmentation. Augmentation is a drug-induced increase in symptom severity defined as an earlier than usual onset of symptoms by 2 hours or by at least two of the following: shorter time to symptom onset following rest, spreading of symptoms to other body parts (arms, trunk, and face), shorter duration of relief from treatment, new or worsening periodic limb movements in sleep, or either medication increase (making symptoms worse) or decrease (making them better).
The incidence of augmentation has been shown to vary with the type of dopaminergic agent (dopamine agonists and levodopa) and also between studies. Earlier studies have reported that augmentation is more likely to occur with levodopa than with dopamine agonists. The incidence of augmentation has been shown to range from 24 to 73 percent in patients on levodopa treatment, from 8 to 33 percent in patients on pramipexole, and from 3 to 24 percent in patients on ropinirole (Allen et al., 2011). Augmentation is suggested to lead to poorer outcomes or to result in a switch to other classes of medication or discontinuation of treatment.
Augmentation usually resolves when the medication that triggered augmentation has been discontinued or when the patient has been switched to another class of medication.
References
Allen RP, Adler CH, Du W, et al. Restless legs syndrome (RLS) augmentation associated with dopamine agonist and levodopa usage in a community sample. Sleep Med May;12(5): PMID:
Garcia-Borreguero D, Hogl B, Ferini-Strambi L, et al. Systematic Evaluation of augmentation during treatment with ropinirole in restless legs syndrome (Willis-Ekbom disease): results from a prospective, multicenter study over 66 weeks. Mov Disord Feb;27(2): PMID:
Wilt TJ, MacDonald R, Ouellette J, et al. Treatment for Restless Legs Syndrome. Evidence Report No. 86 (Prepared by the Minnesota Evidence-based Practice Center under Contract No I). AHRQ Publication No. 12(13)-EHC147-EF. Rockville, MD: Agency for Healthcare Research and Quality; November Available at
Allen RP, Adler CH, Du W, et al. Sleep Med May;12(5): PMID:
Garcia-Borreguero D, Hogl B, Ferini-Strambi L, et al. Mov Disord Feb;27(2): PMID:
Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86.
Available at

9. Background: Uncertainties Related to the Treatment of Restless Legs Syndrome
Clinicians face uncertainty in:
Defining and diagnosing restless legs syndrome (RLS)
In primary care, standard RLS diagnostic criteria may be less consistently applied, resulting in misdiagnosis, misclassification, and unnecessary or ineffective therapy.
Measuring disease severity
The lack of well-defined measures for assessing disease severity and treatment- induced changes in disease status present challenges in clinical practice.
Assessing the risks/benefits of treatment
The relative risks/benefits of the various therapies for RLS—particularly in patients with mild disease and in older adults and children—are unclear.
Background: Uncertainties Related to the Treatment of Restless Legs Syndrome
Clinicians face uncertainty in defining and diagnosing restless legs syndrome (RLS), in assessing disease severity, and in evaluating the risk/benefits of treatment. While these challenges apply to both primary care and specialty settings, they may be more pronounced in primary care.
Defining and diagnosing RLS. Several conditions such as periodic limb movements, positional discomfort, and arthritis “mimic” RLS and should be carefully ruled out during diagnosis. The use of standard RLS diagnostic criteria might be common in specialty practice or in research settings but might not be consistently used in primary care. This might result in patients being misdiagnosed or misclassified or not receiving the appropriate care.
Measuring disease severity. The lack of well-defined measures for assessing disease severity and treatment-induced changes in disease status present challenges in clinical practice. In research settings, these assessments are made using specific rating scales such as the International Restless Legs Syndrome Rating Scale and the Clinical Global Impressions scale. However, the results of RLS severity scales cannot be meaningfully interpreted in the absence of clearly defined “minimum clinically important differences.”
Evaluating the risks and/or benefits of treatment. Since the clinical significance of RLS is due to its impact on an individual’s quality of life and function, treatments should focus on the balance of symptomatic benefits with treatment harms. However, the relative benefits and/or risks of pharmacologic and nonpharmacologic therapies for RLS are unclear. Additionally, the benefits and or harms of these therapies in patients with mild disease and in older adults and children remain to be elucidated.
Reference
Wilt TJ, MacDonald R, Ouellette J, et al. Treatment for Restless Legs Syndrome. Evidence Report No. 86 (Prepared by the Minnesota Evidence-based Practice Center under Contract No I). AHRQ Publication No. 12(13)-EHC147-EF. Rockville, MD: Agency for Healthcare Research and Quality; November Available at
Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86.
Available at

10. Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review (CER) Development
Topics are nominated through a public process, which includes submissions from health care professionals, professional organizations, the private sector, policymakers, members of the public, and others.
A systematic review of all relevant clinical studies is conducted by independent researchers, funded by AHRQ, to synthesize the evidence in a report summarizing what is known and not known about the select clinical issue. The research questions and the results of the report are subject to expert input, peer review, and public comment.
The results of these reviews are summarized into Clinician Research Summaries and Consumer Research Summaries for use in decisionmaking and in discussions with patients. The Research Summaries and the full report, with references for included and excluded studies, are available at
Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review (CER) Development
Topics are nominated through a public process, which includes submissions from health care professionals, professional organizations, the private sector, policymakers, members of the public, and others. A systematic review of all relevant clinical studies is conducted by independent researchers, funded by AHRQ, to synthesize the evidence in a report summarizing what is known and not known about the select clinical issue. The research questions and the results of the report are subject to expert input, peer review, and public comment. The results of these reviews are summarized into Clinician Research Summaries and Consumer Research Summaries for use in decisionmaking and in discussions with patients. The Research Summaries and the full report, with references for included and excluded studies, are available at
Reference
Wilt TJ, MacDonald R, Ouellette J, et al. Treatment for Restless Legs Syndrome. Evidence Report No. 86 (Prepared by the Minnesota Evidence-based Practice Center under Contract No I). AHRQ Publication No. 12(13)-EHC147-EF. Rockville, MD: Agency for Healthcare Research and Quality; November Available at
Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86.
Available at

11. Clinical Questions Addressed by This Comparative Effectiveness Review (1 of 3)
Key Question 1. What is the comparative effectiveness of treatments for restless legs syndrome (RLS)?
What are the benefits from RLS treatments when compared with placebo or no treatment?
What are the benefits from RLS treatments when compared with other active treatments?
What are the durability and
Clinical Questions Addressed by This Comparative Effectiveness Review (1 of 3)
This comparative effectiveness review attempted to address three key questions. Key Question (KQ) 1 is listed in this slide.
KQ 1. What is the comparative effectiveness of treatments for restless legs syndrome (RLS)?
What are the benefits from RLS treatments when compared with placebo or no treatment?
What are the benefits from RLS treatments when compared with other active treatments?
What are the durability and sustainability of treatment benefits?
Reference
Wilt TJ, MacDonald R, Ouellette J, et al. Treatment for Restless Legs Syndrome. Evidence Report No. 86 (Prepared by the Minnesota Evidence-based Practice Center under Contract No I). AHRQ Publication No. 12(13)-EHC147-EF. Rockville, MD: Agency for Healthcare Research and Quality; November Available at
Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86.
Available at

12. Clinical Questions Addressed by This Comparative Effectiveness Review (2 of 3)
Key Question 2. What are the harms of restless legs syndrome (RLS) treatment?
What are the harms from RLS treatments when compared with placebo or no treatment?
What are the harms from RLS treatments when compared with other active treatments?
What are the long-term harms from RLS treatment?
Clinical Questions Addressed by This Comparative Effectiveness Review (2 of 3)
This comparative effectiveness review attempted to address three key questions. Key Question (KQ) 2 is listed on this slide:
KQ 2. What are the harms of restless legs syndrome (RLS) treatment?
What are the harms from RLS treatments when compared with placebo or no treatment?
What are the harms from RLS treatments when compared with other active treatments?
What are the long-term harms from treatment?
Reference
Wilt TJ, MacDonald R, Ouellette J, et al. Treatment for Restless Legs Syndrome. Evidence Report No. 86 (Prepared by the Minnesota Evidence-based Practice Center under Contract No I). AHRQ Publication No. 12(13)-EHC147-EF. Rockville, MD: Agency for Healthcare Research and Quality; November Available at
Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86.
Available at

13. Clinical Questions Addressed by This Comparative Effectiveness Review (3 of 3)
Key Question 3. What are the effects of patient characteristics (age, sex, race, comorbidities, disease severity, etiology, iron status, pregnancy, and end-stage renal disease) on the benefits and harms of treatments for restless legs syndrome?
Clinical Questions Addressed by This Comparative Effectiveness Review (3 of 3)
This comparative effectiveness review attempted to address three key questions. Key Question (KQ) 3 is listed on this slide:
KQ 3. What are the effects of patient characteristics (age, sex, race, comorbidities, disease severity, etiology, iron status, pregnancy, and end-stage renal disease) on the benefits and harms of treatments for restless legs syndrome?
Reference
Wilt TJ, MacDonald R, Ouellette J, et al. Treatment for Restless Legs Syndrome. Evidence Report No. 86 (Prepared by the Minnesota Evidence-based Practice Center under Contract No I). AHRQ Publication No. 12(13)-EHC147-EF. Rockville, MD: Agency for Healthcare Research and Quality; November Available at
Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86.
Available at

14. Rating the Strength of Evidence From the Comparative Effectiveness Review
The strength of evidence was classified into four broad categories:
High
Further research is very unlikely to change the confidence in the estimate of effect.
Moderate
Further research may change the confidence in the estimate of effect and may change the estimate.
Low
Further research is likely to change the confidence in the estimate of effect and is likely to change the estimate.
Insufficient
Evidence either is unavailable or does not permit a conclusion.
Rating the Strength of Evidence From the Comparative Effectiveness Review
Throughout this slide set, strength-of-evidence ratings are assigned to findings of the report. Strength of evidence is typically assigned to reviews of medical treatments after assessing four domains: risk of bias, consistency, directness, and precision. Although these categories were developed to assess the strength of treatment studies, the domains also apply to studies of prevalence and screening. Available evidence for each Key Question (KQ) was assessed for each of these four domains; the domains were combined qualitatively to develop the strength of evidence for each KQ.
Reference
Wilt TJ, MacDonald R, Ouellette J, et al. Treatment for Restless Legs Syndrome. Evidence Report No. 86 (Prepared by the Minnesota Evidence-based Practice Center under Contract No I). AHRQ Publication No. 12(13)-EHC147-EF. Rockville, MD: Agency for Healthcare Research and Quality; November Available at
Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86.
Available at

15. Pharmacologic Therapies for Restless Legs Syndrome Assessed in This Review
Treatment*
Generic Name
Brand Name
FDA Approval for RLS
Dopaminergic agents
Levodopa
Dopar® No
Ropinirole
Requip®
Yes
Pramipexole
Mirapex®
Rotigotine patch
Neupro®
Anticonvulsants (alpha-2-delta ligands)
Gabapentin enacarbil
Horizant®
Gabapentin
Neurontin®
Pregabalin
Lyrica®
Iron
Many formulations –
* Sedative hypnotics and opioids were included in this review; however, no eligible studies were identified that assessed these agents in patients with restless legs syndrome (RLS). Sedative hypnotics and opioids have not been approved by the U.S. Food and Drug Administration (FDA) as treatment for RLS.
Pharmacologic Therapies for Restless Legs Syndrome Assessed in This Review
The table in this slide lists the pharmacologic therapies for restless legs syndrome (RLS) that were assessed in this review and their U.S. Food and Drug Administration (FDA) approval status. Therapies assessed included dopaminergic agents (levodopa, ropinirole, pramipexole, and rotigotine), alpha-2-delta ligands (gabapentin enacarbil, gabapentin, and pregabalin) and iron (many formulations). Of these, the dopaminergic agents ropinirole, pramipexole, and rotigotine and the alpha-2-delta ligand gabapentin enacarbil have been approved by the FDA as treatment for RLS.
Reference
Wilt TJ, MacDonald R, Ouellette J, et al. Treatment for Restless Legs Syndrome. Evidence Report No. 86 (Prepared by the Minnesota Evidence-based Practice Center under Contract No I). AHRQ Publication No. 12(13)-EHC147-EF. Rockville, MD: Agency for Healthcare Research and Quality; November Available at
Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86.
Available at

16. Evidence for the Benefits of Pharmacologic Interventions in Treating Restless Legs Syndrome: Dopaminergic Agents
When compared with placebo, dopamine agonists (ropinirole, pramipexole, and rotigotine):
Increased the percentage of patients with a clinically important response*
Reduced restless legs syndrome symptoms
Improved disease-specific quality of life and patient-reported sleep outcomes
Strength of Evidence: High
Evidence from one study suggested that cabergoline** improved symptom scores on the International Restless Legs Syndrome Rating Scale and the Restless Legs Syndrome Quality of Life Scale more than levodopa.
Strength of Evidence: Moderate
Evidence for the Benefits of Pharmacologic Interventions in Treating Restless Legs Syndrome: Dopaminergic Agents
Seven trials (3 pramipexole trials, n = 1,007; 4 rotigotine trials, n = 1,139) reported the percentage of patients with restless legs syndrome (RLS) who responded to treatment based on a >50-percent reduction in the International Restless Legs Syndrome (IRLS) Rating Scale symptom score from baseline. When compared with placebo, the percentage of patients with a favorable treatment response was greater with the dopamine agonists pramipexole and rotigotine (risk ratio [RR]=1.60; 95-percent confidence interval [95% CI], 1.38 to 1.86]). The absolute effect in terms of responders per 100 patients was 24 more (95% CI, 15 more to 35 more) in the dopamine agonist treatment group than with placebo. The strength of evidence for this finding was rated high.
The proportion of responders (with a rating of “much improved” or “very much improved”) on clinician-reported and patient-reported global scales was higher for dopamine agonists than for placebo (respective RRs, 1.45 [95% CI, 1.36 to 1.55] and 1.66 [95% CI, 1.45 to 1.90]). The overall strength of evidence for both of these outcomes was high.
Dopamine agonists improved RLS-specific quality of life as measured by standardized mean differences (SMDs) in Johns Hopkins RLS Quality of Life Scale scores (n = 2140). The effect size is considered small to medium in magnitude (SMD = -0.37; 95% CI, to -0.27). The strength of evidence for this finding was rated high.
Dopamine agonists improved patient-reported sleep quality when compared with placebo as measured by the Medical Outcomes Study Sleep Problem Index scale (standardized mean effect size = 0.38; 95% CI, 0.29 to 0.46). The magnitude of effect was considered small to moderate, and the strength of evidence was high.
One 30-week study (n = 361) found that the dopamine agonist cabergoline improved IRLS Rating Scale symptom scores (weighted mean difference [WMD] = -6.80; 95% CI, to -4.58) and RLS quality of life more than levodopa (WMD = -7.10; 95% CI, to -4.26]) in white adults with severe RLS (IRLS Rating Scale symptom score = 25.7). The strength of evidence for this finding was moderate.
Reference
Wilt TJ, MacDonald R, Ouellette J, et al. Treatment for Restless Legs Syndrome. Evidence Report No. 86 (Prepared by the Minnesota Evidence-based Practice Center under Contract No I). AHRQ Publication No. 12(13)-EHC147-EF. Rockville, MD: Agency for Healthcare Research and Quality; November Available at
* These are patients with a greater than 50-percent reduction in symptom scores on the International RLS Rating Scale or who were “improved” or “much improved” on the Clinical Global Impressions Scale.
** Cabergoline is not approved by the U.S. Food and Drug Administration (FDA) as treatment for RLS and is rarely used in the United States because of FDA warnings about cardiac valvular complications.
Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86.
Available at

17. Outcomes and Strength of Evidence in Placebo-Controlled Studies of Dopamine Agonists (1 of 2)
Outcome With Treatment vs. Placebo
SOE
RLS Treatment Compared With Placebo
No. of Trials n
Summary Statistics
(95% CI)
Absolute Effect per 100 Patients
Increase in IRLS Rating Scale Responders (>50% score reduction)
High
Pramipexole 3
1,079
RR 1.46 (1.22–1.74)
21 more per 100
(10 to 34 more)
Rotigotine 4
1,139
RR 1.76 (1.47–2.100)
25 more per 100
(16 to 37 more)
Increase in Clinical Global Impressions Scale Responders (much or very much improved) 5
1,747
RR 1.61 (1.4–1.86)
(17 to 36 more)
Ropinirole 6
1,608
RR 1.37 (1.25–1.50)
18 more per 100
(12 to 24 more)
1,091
RR 1.37 (1.22–1.54)
19 more per 100
(12 to 28 more)
Improvement in Patient-Reported RLS Quality
of Life
912
SMD (-0.61 to -0.25)
Not reported 2
643
SMD (-0.45 to -0.25)
585
SMD (-0.60 to )
Outcomes and Strength of Evidence in Placebo-Controlled Studies of Dopamine Agonists (1 of 2)
The table in this slide lists the individual outcomes in placebo-controlled studies for the various dopamine agonists assessed in this review (pramipexole, ropinirole, and rotigotine). Findings are presented for the following outcomes: International Restless Legs Syndrome Rating Scale responders (>50% score reduction), physician-reported Clinical Global Impressions Scale score (much or very much improved), and the patient-reported RLS Quality of Life score. The strength of evidence for each of the various outcomes is also listed.
Table Abbreviations
95% CI = 95-percent confidence interval
IRLS = International Restless Legs Syndrome
RLS = restless legs syndrome
RR = relative risk
SMD = standardized mean difference
SOE = strength of evidence
Reference
Wilt TJ, MacDonald R, Ouellette J, et al. Treatment for Restless Legs Syndrome. Evidence Report No. 86 (Prepared by the Minnesota Evidence-based Practice Center under Contract No I). AHRQ Publication No. 12(13)-EHC147-EF. Rockville, MD: Agency for Healthcare Research and Quality; November Available at
Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86.
Available at

18. Outcome With Treatment vs. Placebo RLS Treatment Compared With Placebo
Outcomes and Strength of Evidence in Placebo-Controlled Studies of Dopamine Agonists (2 of 2)
Outcome With Treatment vs. Placebo
SOE
RLS Treatment Compared With Placebo
No. of Trials n
Summary Statistics
(95% CI)
Improvement in Patient Self-Rated Sleep Using the MOS-SPI-II Scale
High
Pramipexole 1
356
SMD (-0.60 to -0.13)
Ropinirole 4
1,237
SMD (-0.24 to -0.49)
Rotigotine 3
459
SMD (-0.24 to -0.61)
Increase in Study Withdrawals Due to an Adverse Event
Moderate 5
1,791
RR 0.97 (0.69–1.35) 7
1,698
RR 1.48 (0.99–2.20)
1,370
RR 1.37 (1.33–4.70)
Increase in Number of Patients With >1 Adverse Event
1,790
RR 1.16 (1.04–1.29)
1,695
RR 1.20 (1.10–1.32)
1,369
RR 1.25 (1.00–1.59)
Outcomes and Strength of Evidence in Placebo-Controlled Studies of Dopamine Agonists (2 of 2)
The table in this slide lists the individual outcomes in placebo-controlled studies for the various dopamine agonists (pramipexole, ropinirole, and rotigotine) assessed in this review. Findings are presented for the following outcomes: self-rated sleep using the Medical Outcomes Scale–Sleep Problems Index II Scale, study withdrawals due to an adverse event, and patients with >1 adverse event. The strength of evidence for each of the various outcomes is also listed.
Table Abbreviations
95% CI = 95-percent confidence interval
MOS-SPI-II = Medical Outcomes Scale–Sleep Problems Index II
RR = relative risk
SMD = standardized mean difference
SOE = strength of evidence
Reference
Wilt TJ, MacDonald R, Ouellette J, et al. Treatment for Restless Legs Syndrome. Evidence Report No. 86 (Prepared by the Minnesota Evidence-based Practice Center under Contract No I). AHRQ Publication No. 12(13)-EHC147-EF. Rockville, MD: Agency for Healthcare Research and Quality; November Available at
Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86.
Available at

19. Evidence for the Benefits of Pharmacologic Interventions in Treating Restless Legs Syndrome: Alpha-2-Delta Ligands
When compared with placebo, alpha-2-delta ligands (gabapentin enacarbil and pregabalin):
Increased the percentage of patients with a clinically important response
Strength of Evidence: High
Improved disease-specific quality of life and patient-reported sleep outcomes
Strength of Evidence: Low
Gabapentin enacarbil improved sleep adequacy based on the sleep adequacy domain of the Medical Outcomes Study.
Evidence for the Benefits of Pharmacologic Interventions in Treating Restless Legs Syndrome: Alpha-2-Delta Ligands
Three trials evaluated International Restless Legs Syndrome (IRLS) Rating Scale responders. Gabapentin enacarbil and pregabalin, when compared with placebo, significantly increased the percentage of IRLS Rating Scale responders (relative risk [RR] = 1.66; 95-percent confidence interval [95% CI], 1.33 to 2.09]). The absolute effect in terms of responders per 100 patients was 25 more (95% CI, 12 more to 41 more). The strength of evidence for this finding was rated high.
Studies also showed that the proportion of patients who reported improvement or very much improvement on the Clinical Global Impression Scale was significantly greater for gabapentin enacarbil and pregabalin groups when compared with placebo, though there was evidence of heterogeneity between treatment subgroups (RR = 1.60; 95% CI, 1.21 to 2.10). The strength of evidence for this finding was rated high.
Two trials showed mixed results on quality-of-life measures (standardized mean difference [SMD] = 0.27; 95% CI, to 0.70). One fixed-dose study of pregabalin found no statistically significant improvement in scores on the Restless Legs Syndrome Quality of Life questionnaire (RLS-QoL) with any dose versus placebo over a 6-week period (k = 1, n = 122). Gabapentin enacarbil improved RLS-QoL scores at week 12 when compared with placebo (mean [standard deviation] change from baseline: gabapentin enacarbil, 21.4 [17.00]; placebo, 14.1 [17.32]; RLS treatment difference 7.8 [P < ]; SMD = 0.42 [95% CI, 0.16 to 0.69]). The strength of evidence was low.
In two trials, treatment with gabapentin enacarbil significantly improved sleep adequacy based on the pooled scores from the Medical Outcomes Study–Sleep Adequacy Domain (SMD = 0.53; 95% CI, 0.33 to 0.72; k = 2). The magnitude of effect was considered moderate, and the strength of evidence was high.
Reference
Wilt TJ, MacDonald R, Ouellette J, et al. Treatment for Restless Legs Syndrome. Evidence Report No. 86 (Prepared by the Minnesota Evidence-based Practice Center under Contract No I). AHRQ Publication No. 12(13)-EHC147-EF. Rockville, MD: Agency for Healthcare Research and Quality; November Available at
Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86.
Available at

20. Outcomes and Strength of Evidence in Placebo-Controlled Studies of Alpha-2-Delta Ligands (1 of 2)
Outcome With Treatment vs. Placebo
SOE
RLS Treatment Compared With Placebo
No. of Trials n
Summary Statistics
(95% CI)
Absolute Effect per 100 Patients
Increase in IRLS Rating Scale Responders (>50% score reduction)
High
Gabapentin enacarbil 1
321
RR 1.54 (1.18–2.01)
21 more per 100
(7 to 40 more)
Pregabalin 2
182
RR 2.03 (1.33–3.11)
34 more per 100
(11 to 69 more)
Increase in Clinical Global Impressions Scale Responders (much–very much improved)
431
RR 1.80 (1.51–2.14)
33 more per 100
(21 to 48 more) 44
RR 1.14 (0.80–1.6)
9 more per 100
(12 fewer to 40 more)
Improvement in RLS Quality
of Life
Low
538
SMD 0.42 (0.16 to 0.69)
Not reported
124
SMD (-0.65 to -0.55)
Outcomes and Strength of Evidence in Placebo-Controlled Studies of Alpha-2-Delta Ligands (1 of 2)
The table in this slide lists the individual outcomes in placebo-controlled studies for the various alpha-2-delta ligands—gabapentin enacarbil and pregabalin—assessed in this review. Findings are presented for the following outcomes: International Restless Legs Syndrome Rating Scale responders (>50% score reduction), physician-reported Clinical Global Impressions Scale score (much or very much improved), and the patient-reported Restless Legs Syndrome Quality of Life Scale score. The strength of evidence for each of the various outcomes is also listed.
Table Abbreviations
95% CI = 95-percent confidence interval
IRLS = International Restless Legs Syndrome
RLS = restless legs syndrome
RR = relative risk
SMD = standardized mean difference
SOE = strength of evidence
Reference
Wilt TJ, MacDonald R, Ouellette J, et al. Treatment for Restless Legs Syndrome. Evidence Report No. 86 (Prepared by the Minnesota Evidence-based Practice Center under Contract No I). AHRQ Publication No. 12(13)-EHC147-EF. Rockville, MD: Agency for Healthcare Research and Quality; November Available at
Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86.
Available at

21. Outcome With Treatment vs. Placebo RLS Treatment Compared With Placebo
Outcomes and Strength of Evidence in Placebo-Controlled Studies of Alpha-2-Delta Ligands (2 of 2)
Outcome With Treatment vs. Placebo
SOE
RLS Treatment Compared With Placebo
No. of Trials n
Summary Statistics
(95% CI)
Improvement in Self-Rated Sleep Using the MOS-SPI-II Scale
High
Gabapentin enacarbil 2
431
SMD 0.53 (-0.33 to 0.72)
Increase in Number of Patients With >1 Adverse Event
Moderate 5
738
RR 1.09 (1.00–1.19)
Pregabalin 7
195
RR 1.67 (0.74–3.80)
Outcomes and Strength of Evidence in Placebo-Controlled Studies of Alpha-2-Delta Ligands (2 of 2)
The table in this slide lists the individual outcomes in placebo-controlled studies for the various alpha-2-delta ligands—gabapentin enacarbil and pregabalin—assessed in this review. Findings are presented for the following outcomes: self-rated sleep using the Medical Outcomes Scale–Sleep Problems Index II Scale and patients with >1 adverse event. The strength of evidence for each of the various outcomes is also listed.
Reference
Wilt TJ, MacDonald R, Ouellette J, et al. Treatment for Restless Legs Syndrome. Evidence Report No. 86 (Prepared by the Minnesota Evidence-based Practice Center under Contract No I). AHRQ Publication No. 12(13)-EHC147-EF. Rockville, MD: Agency for Healthcare Research and Quality; November Available at
Abbreviations: 95% CI = 95-percent confidence interval; MOS-SPI-II = Medical Outcomes Scale–Sleep Problems Index II; RR = relative risk; SMD = standardized mean difference; SOE = strength of evidence
Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86.
Available at

22. Evidence for the Benefits of Pharmacologic Interventions in Treating Restless Legs Syndrome: Iron Therapy
Results from a small, good-quality study showed that when compared with placebo, intravenous ferric carboxymaltose:
Improved symptom scores on the International Restless Legs (IRLS) Syndrome Rating Scale and the Restless Legs Syndrome Quality of Life Scale
Strength of Evidence: Moderate
Improved patient-reported sleep outcomes
Strength of Evidence: Low
Two small trials of iron therapy versus placebo in adults with iron deficiency suggested that iron may improve the percentage of adults considered IRLS Rating Scale responders and symptom scores on the IRLS Rating Scale.
Evidence for the Benefits of Pharmacologic Interventions in Treating Restless Legs Syndrome: Iron Therapy
One small good-quality short-term randomized controlled trial (RCT; n = 46) found that intravenous iron (ferric carboxymaltose) improved symptom scores on the International Restless Legs Syndrome (IRLS) Rating Scale and disease-specific quality of life when compared with placebo over 28 days of therapy. Mean improvements in scores on the IRLS Rating Scale for iron and placebo were reductions of 8.9 and 4.0 points, respectively, with a mean difference of (95-percent confidence interval [95% CI], to ). The strength of evidence for these findings was determined to be moderate.
In the small, good-quality study described above, intravenous ferric carboxymaltose was also found to improve patient-reported sleep outcomes. The strength of evidence for this outcome was low.
Two small good-quality RCTs evaluated iron therapy (one intravenous and one oral) in patients with restless legs syndrome secondary to iron deficiency. One 12-week trial of 18 subjects found that when compared with placebo, iron reduced symptoms scores on the IRLS Rating Scale by 9.16 points (95% CI, to -3.1). Another trial of intravenous iron sucrose administered five times over 3 months in 60 subjects found no difference versus placebo at 12 months in mean change in IRLS Rating Scale symptom scores (p = 0.47). A post hoc analysis at 11 weeks found an increase in the percentage of subjects considered IRLS Rating Scale responders among those randomized to iron (RR = 1.85; [95% CI, 1.07 to 3.18]). The strength of evidence for these outcomes was low.
Reference
Wilt TJ, MacDonald R, Ouellette J, et al. Treatment for Restless Legs Syndrome. Evidence Report No. 86 (Prepared by the Minnesota Evidence-based Practice Center under Contract No I). AHRQ Publication No. 12(13)-EHC147-EF. Rockville, MD: Agency for Healthcare Research and Quality; November Available at
Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86.
Available at

23. Evidence for the Benefits of Pharmacologic Interventions in Treating Restless Legs Syndrome: Opioids and Hypnotics
No eligible studies assessed opioids or sedative hypnotics, though these are used clinically as treatment for restless legs syndrome.
Strength of Evidence: Insufficient
Evidence for the Benefits of Pharmacologic Interventions in Treating Restless Legs Syndrome: Opioids and Hypnotics
For individuals unable to initiate or tolerate dopaminergic agents or for whom these drugs have failed, available pharmacologic treatments include off-label opioids (morphine, oxycodone, and methadone), sedative hypnotics, and tramadol. None of these drugs are approved by the U.S. Food and Drug Administration as treatment for restless legs syndrome (RLS), and all have the potential for long-term abuse, especially given the subjective nature of RLS symptoms and the large placebo response seen in other pharmacologic studies. This review identified no studies meeting the inclusion criteria that assessed opioids, sedative hypnotics, or tramadol, all of which are listed in treatment algorithms and presumably used in clinical practice.
Reference
Wilt TJ, MacDonald R, Ouellette J, et al. Treatment for Restless Legs Syndrome. Evidence Report No. 86 (Prepared by the Minnesota Evidence-based Practice Center under Contract No I). AHRQ Publication No. 12(13)-EHC147-EF. Rockville, MD: Agency for Healthcare Research and Quality; November Available at
Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86.
Available at

24. Evidence for the Benefits of Nonpharmacologic Interventions in Treating Restless Legs Syndrome (1 of 2)
When compared with sham treatment, pneumatic compression devices:
Improved symptom scores on the International Restless Legs Syndrome (IRLS) Rating Scale
Improved quality of life
Reduced daytime somnolence
Achieved better symptom resolution
Strength of Evidence: Moderate
Near-infrared light treatment improved symptom scores on the IRLS Rating Scale more than sham treatment.
Strength of Evidence: Low
Evidence for the Benefits of Nonpharmacologic Interventions in Treating Restless Legs Syndrome (1 of 2)
A good-quality randomized controlled trial (RCT) assessed pneumatic compression devices versus sham devices worn for at least 1 hour each day for 4 weeks before symptoms typically began. Pneumatic compression devices were programmed to inflate the leg wraps for 5 seconds every minute. The only difference between the intervention and sham devices was that the therapeutic devices generated 40 cm H2O of air pressure with each inflation cycle, while sham devices generated a 3 to 4 cm H2O rise in pressure. Results showed better end-of-study (4 weeks) IRLS Rating Scale symptom scores (8.4 +/- 3.4 vs /- 3.9; p = 0.006), dimensions of the Johns Hopkins Restless Legs Syndrome Quality of Life instrument (P < 0.05 for all four dimensions), and daytime somnolence measures as assessed by the Epworth Sleepiness Scale (6.5 +/- 4.0 vs /- 3.8; p = 0.04) and complete resolution of symptoms (8 [38.1%] vs. 0 [0%]; p = 0.007) more than sham devices. The strength of evidence for these findings was rated moderate.
In one low-quality RCT, 21 of 34 patients were evaluated with near-infrared light treatment in comparison with sham treatment. Twelve 30-minute near-infrared light treatment sessions were applied over 4 weeks. Near-infrared light treatment significantly improved IRLS Rating Scale symptom scores more than sham (-13.4 points vs points, respectively), with a mean deviation of (95-percent confidence interval, to -4.79). The strength of evidence was low.
Reference
Wilt TJ, MacDonald R, Ouellette J, et al. Treatment for Restless Legs Syndrome. Evidence Report No. 86 (Prepared by the Minnesota Evidence-based Practice Center under Contract No I). AHRQ Publication No. 12(13)-EHC147-EF. Rockville, MD: Agency for Healthcare Research and Quality; November Available at
Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86.
Available at

25. Evidence for the Benefits of Nonpharmacologic Interventions in Treating Restless Legs Syndrome (2 of 2)
Strength training and treadmill walking improved scores on the International Restless Legs Syndrome Rating Scale, but adherence to both types of exercise was poor.
Strength of Evidence: Low
The botanical extract valerian was not effective in treating restless legs syndrome.
Evidence for the Benefits of Nonpharmacologic Interventions in Treating Restless Legs Syndrome (2 of 2)
In one fair-quality study, treadmill walking and lower body resistance exercise performed three times weekly for 12 weeks improved International Restless Legs Syndrome (IRLS) Rating Scale scores (weighted mean difference = -9.4 [95-percent confidence interval, to -4.9]) when compared with usual care (low quality of evidence). However, the authors reported results for only 28 subjects who completed treatment out of the 41 subjects who had enrolled. The strength of evidence for this finding was rated low.
A fair-quality randomized controlled trial of the botanical preparation valerian at 800 mg daily for 8 weeks did not improve IRLS Rating Scale symptom scores (p = 0.69), Pittsburgh Sleep Quality Index scores (p = 0.94), or Epworth Sleepiness Scale scores (0.64) more than placebo among 48 adults with severe restless legs syndrome symptoms (mean IRLS Rating Scale scores = 23.5) occurring at least three times per week. The strength of evidence was rated low.
Reference
Wilt TJ, MacDonald R, Ouellette J, et al. Treatment for Restless Legs Syndrome. Evidence Report No. 86 (Prepared by the Minnesota Evidence-based Practice Center under Contract No I). AHRQ Publication No. 12(13)-EHC147-EF. Rockville, MD: Agency for Healthcare Research and Quality; November Available at
Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86.
Available at

26. Evidence for the Harms of Pharmacologic Interventions in Treating Restless Legs Syndrome: Dopaminergic Agents (1 of 2)
Study withdrawals due to adverse effects were more common with dopamine agonist treatments than with placebo.
The differences were mainly due to an increase in withdrawals related to adverse effects reported in studies of transdermal rotigotine.
Strength of Evidence: Moderate
More patients randomized to dopamine agonists had at least one adverse effect when compared with those randomized to placebo.
Strength of Evidence: High
Evidence for the Harms of Pharmacologic Interventions in Treating Restless Legs Syndrome: Dopaminergic Agents (1 of 2)
There was an overall significant increase in study withdrawals due to adverse effects associated with dopamine agonist treatment (10% vs. 6%; relative risk [RR] =1.37; 95-percent confidence interval [95% CI], 1.03 to 1.82). The strength of evidence for this finding was rated moderate. Risk of withdrawal due to adverse events appeared to differ between dopamine agonists (I2 = 73%, p = 0.02), with the highest increase associated with rotigotine therapy (RR = 2.50 [95% CI, 1.33 to 4.70]).
More patients reported at least one adverse effect with a dopamine agonist when compared with placebo (RR = 1.19; 95% CI, 1.12 to 1.28). The strength of evidence for this finding was rated high.
Reference
Wilt TJ, MacDonald R, Ouellette J, et al. Treatment for Restless Legs Syndrome. Evidence Report No. 86 (Prepared by the Minnesota Evidence-based Practice Center under Contract No I). AHRQ Publication No. 12(13)-EHC147-EF. Rockville, MD: Agency for Healthcare Research and Quality; November Available at
Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86.
Available at

27. Evidence for the Harms of Pharmacologic Interventions in Treating Restless Legs Syndrome: Dopaminergic Agents (2 of 2)
Short-term adverse effects from dopamine agonist treatment included nausea, vomiting, somnolence, and fatigue.
Strength of Evidence: High
Evidence from observational studies suggests that augmentation is common across dopaminergic agents (dopamine agonists and levodopa), with prevalence estimates ranging from 2.3 to 60 percent.*
The prevalence estimates of augmentation were higher in studies of levodopa when compared with studies of dopamine agonists.
The reason for the wide variation in prevalence estimates across drugs is unclear.
* This finding was not rated.
Evidence for the Harms of Pharmacologic Interventions in Treating Restless Legs Syndrome: Dopaminergic Agents (2 of 2)
Short-term adverse effects from treatment with dopamine agonists, when compared with placebo, were nausea (23% vs. 7%; relative risk [RR] = 3.31; 95-percent confidence interval [95% CI], 2.53 to 4.33), vomiting (7% vs. 2%; RR = 4.48; 95% CI, 2.68 to 7.4), and somnolence (12% vs. 6%, RR = 2.04; 95% CI, 1.50 to 2.76). Application site reactions were much more common with transdermal rotigotine than with placebo (29% vs. 3%; RR = 8.32; 95% CI, 3.45 to 20.05). The strength of evidence for all these outcomes was rated high.
Long-term augmentation was reported in 15 observational studies (including open-label extensions of randomized controlled trials), all of which involved dopamine agonists or levodopa. In general, augmentation was common across dopaminergic or dopamine agonist drugs. Two small studies of levodopa reported that augmentation occurred in 35 to 60 percent of individuals over 6 to 12 months. Six studies of pramipexole with followup durations of 6 months to 10 years reported augmentation in 7 to 33 percent of individuals. Augmentation was reported in 10 and 23 percent of individuals treated with rotigotine at 1 and 5 years of followup. A single study of ropinirole with a followup of 1 year reported that only 2.3 percent of individuals experienced augmentation. The prevalence estimates of augmentation were higher in studies of levodopa when compared with studies of other dopamine agonists. It is not clear why period prevalence estimates varied widely across drugs or time periods.
Reference
Wilt TJ, MacDonald R, Ouellette J, et al. Treatment for Restless Legs Syndrome. Evidence Report No. 86 (Prepared by the Minnesota Evidence-based Practice Center under Contract No I). AHRQ Publication No. 12(13)-EHC147-EF. Rockville, MD: Agency for Healthcare Research and Quality; November Available at
Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86.
Available at

28. Evidence for the Harms of Pharmacologic Interventions in Treating Restless Legs Syndrome: Alpha-2-Delta Ligands
Short-term adverse effects such as somnolence, unsteadiness or dizziness, and dry mouth were much more common with alpha-2-delta ligands than with placebo.
Strength of Evidence: High
Study withdrawals due to adverse effects was marginally greater in patients receiving alpha-2-delta ligand treatment versus placebo.
Strength of Evidence: Moderate
Evidence for the Harms of Pharmacologic Interventions in Treating Restless Legs Syndrome: Alpha-2-Delta Ligands
Short-term adverse effects that were significantly greater with alpha-2-delta ligand treatment when compared with placebo were somnolence (19% vs. 3%; relative risk [RR] = 5.37; 95-percent confidence interval [95% CI], 2.38 to 12.12), unsteadiness or dizziness (17% vs. 4%; RR = 4.11; 95% CI, 2.19 to 7.71), and dry mouth (6% vs. 1%; RR = 3.31; 95% CI, 1.09 to 10.05). The overall strength of evidence was high for these outcomes.
There was an overall increase in study withdrawals due to adverse effects associated with alpha-2-delta ligand treatment when compared with placebo (8% vs. 4%; RR = 1.86; 95% CI, 0.95 to 3.63). The strength of evidence for this finding was rated moderate.
Reference
Wilt TJ, MacDonald R, Ouellette J, et al. Treatment for Restless Legs Syndrome. Evidence Report No. 86 (Prepared by the Minnesota Evidence-based Practice Center under Contract No I). AHRQ Publication No. 12(13)-EHC147-EF. Rockville, MD: Agency for Healthcare Research and Quality; November Available at
Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86.
Available at

29. Conclusions (1 of 2)
When compared with placebo, dopamine agonists and alpha-2-delta ligands reduce restless legs syndrome (RLS) symptoms and improve patient-reported sleep outcomes and disease-specific quality of life.
Moderate-level evidence suggests benefits of intravenous iron on symptoms of RLS.
No eligible studies assessed opioids or sedative hypnotics for the treatment of RLS.
Some nonpharmacologic interventions such as compression stockings, near-infrared light, and exercise improve RLS symptoms (evidence quality low to moderate).
Conclusions (1 of 2)
Results from small, placebo-controlled randomized trials of generally short duration demonstrated that dopamine agonists (ropinirole, pramipexole, and rotigotine) and anticonvulsant alpha-2-delta ligands (gabapentin enacarbil, gabapentin, and pregabalin) increase the percentage of individuals responding to treatment (as defined by a 50% reduction in the International Restless Legs Syndrome Rating Scale symptom score or reporting “improved or much improved” on the clinician-assessed Global Impressions Scale or on the patient-assessed Global Impressions Scale), reduce restless legs syndrome symptoms, and improve disease-specific quality of life and patient-reported sleep outcomes.
Results from a small, good-quality study showed that intravenous ferric carboxymaltose improved symptom scores on the International Restless Legs Syndrome Rating Scale and the Restless Leg Syndrome Quality of Life Scale when compared with placebo.
No eligible studies were identified that assessed opioids or sedative hypnotics for the treatment of restless legs syndrome (RLS).
Evidence of low to moderate quality suggests that some nonpharmacologic interventions (compression stockings, near-infrared light, or exercise) improve RLS symptoms. This evidence was based mainly on single small studies.
Reference
Wilt TJ, MacDonald R, Ouellette J, et al. Treatment for Restless Legs Syndrome. Evidence Report No. 86 (Prepared by the Minnesota Evidence-based Practice Center under Contract No I). AHRQ Publication No. 12(13)-EHC147-EF. Rockville, MD: Agency for Healthcare Research and Quality; November Available at
Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86.
Available at

30. Conclusions (2 of 2)
Adverse effects of pharmacologic therapies for restless legs syndrome (RLS) and treatment withdrawals due to adverse effects or lack of efficacy are common.
Evidence from observational studies suggests that augmentation is common across dopaminergic agents.
The studies included in this review were conducted in adults with moderate to severe idiopathic RLS.
The effectiveness and applicability of the assessed RLS therapies for adults with milder or less frequent RLS symptoms, individuals with secondary RLS, and children are unknown.
Conclusions (2 of 2)
Adverse effects of pharmacologic therapies and treatment withdrawals due to adverse effects or lack of efficacy are common. Evidence from observational studies suggests that augmentation is common across dopaminergic agents.
The studies included in this review were mainly conducted in adults with moderate to severe idiopathic RLS. Evidence is lacking about the effectiveness in, and applicability to, adults with less severe or less frequent RLS symptoms, children, and individuals with secondary RLS, including those with iron deficiency, those with end-stage renal disease, in pregnant women, or in women intending to become pregnant.
Reference
Wilt TJ, MacDonald R, Ouellette J, et al. Treatment for Restless Legs Syndrome. Evidence Report No. 86 (Prepared by the Minnesota Evidence-based Practice Center under Contract No I). AHRQ Publication No. 12(13)-EHC147-EF. Rockville, MD: Agency for Healthcare Research and Quality; November Available at
Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86.
Available at

31. Gaps in Knowledge (1 of 2)
Most studies included in this review were efficacy studies. The included studies did not permit reliable indirect comparisons about comparative benefits and harms.
The current evidence base consists almost exclusively of pharmacologic treatments. The effectiveness of several nonpharmacologic treatments for restless legs syndrome (RLS) is not known. Additionally, the effectiveness of over-the-counter iron supplements is not known.
No evidence was found from eligible studies about the effectiveness of therapies in specific subgroups such as children, older adults with multiple comorbidities, or individuals with secondary RLS.
Gaps in Knowledge (1 of 2)
The primary intent of this report was to conduct a comparative effectiveness review on treatments for restless legs syndrome (RLS). However, most of the studies included in this review were efficacy studies (studies of treatments vs. placebo). Only two randomized controlled trials were identified that directly compared treatment options. Therefore, included studies did not permit reliable indirect comparisons and, therefore, robust conclusions about comparative benefits and harms.
The studies included in this review mainly assessed pharmacological therapies. Few nonpharmacologic therapies were assessed, and no individual nonpharmacologic treatment was studied in more than a single trial. The effectiveness of nonpharmacologic treatments such as herbal therapy, mind-body medicine, and manipulative treatments is not known. Additionally, the effectiveness of over-the-counter iron supplements is unknown.
Evidence is lacking about the long-term effectiveness in, and applicability to, adults with less severe or less frequent RLS symptoms, children, or individuals with secondary RLS, including those with iron deficiency, those with end-stage renal disease, pregnant women, or women intending to become pregnant.
Reference
Wilt TJ, MacDonald R, Ouellette J, et al. Treatment for Restless Legs Syndrome. Evidence Report No. 86 (Prepared by the Minnesota Evidence-based Practice Center under Contract No I). AHRQ Publication No. 12(13)-EHC147-EF. Rockville, MD: Agency for Healthcare Research and Quality; November Available at
Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86.
Available at

32. Gaps in Knowledge (2 of 2)
The long-term durability of benefits from treatment of restless legs syndrome (RLS) remains unknown.
Augmentation is a significant harm with dopaminergic therapy; yet, little is known about patient characteristics or other risk factors that may lead to augmentation.
The included studies do not consistently report on the use of objective criteria for sleep assessment.
There is a paucity of information on the effects of environmental factors on RLS.
Gaps in Knowledge (2 of 2)
The studies of restless legs syndrome included in this review were mainly short-duration studies (typically 12 weeks long). The long-term effects of the reviewed treatments remains unknown. High-quality, long-term, open-label extension studies from randomized trials that establish the timeframe over which treatment benefits are sustained for different drugs and in specific groups of patients are needed.
The impact of patient characteristics on treatment outcomes have not been assessed in the included studies. In the future, randomized trials that report effectiveness of treatments for subgroups of patients such as those with different disease duration, those new to treatment, and those for whom previous treatment failed have to be conducted.
Augmentation is a significant harm with dopaminergic therapy and can lead to treatment discontinuation; yet, little is known about patient characteristics or other risk factors that may lead to augmentation.
The included studies do not consistently report on the use of objective criteria for sleep assessment.
There is a paucity of information on the effects of environmental factors on restless legs syndrome and their impact on treatment outcomes.
Reference
Wilt TJ, MacDonald R, Ouellette J, et al. Treatment for Restless Legs Syndrome. Evidence Report No. 86 (Prepared by the Minnesota Evidence-based Practice Center under Contract No I). AHRQ Publication No. 12(13)-EHC147-EF. Rockville, MD: Agency for Healthcare Research and Quality; November Available at
Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86.
Available at

33. What To Discuss With Your Patients and Their Caregivers
What restless legs syndrome (RLS) is and that it is a treatable condition
That RLS can become a chronic condition that requires treatment in moderate to severe cases
The available pharmacologic and nonpharmacologic therapies for RLS
The available evidence for the various treatments for RLS* with regard to:
Disease symptoms
Quality of life and sleep outcomes
Adverse effects
The possibility that the patient might develop augmentation if he/she is taking levodopa or dopamine agonists
* However, it should be emphasized that the evidence is based on studies in patients with moderate to severe RLS, and its applicability to patients with mild RLS or with RLS due to other causes is unknown. Data on long-term benefits and harms of treatments are lacking.
What To Discuss With Your Patients and Their Caregivers
Issues you should discuss with your patients and their caregivers regarding treatments for restless legs syndrome (RLS) include:
What RLS is and that it is a treatable condition
That RLS can become a chronic condition that requires treatment in moderate to severe cases
The currently available pharmacologic and nonpharmacologic therapies for RLS
The available evidence for the effectiveness of the various treatments for RLS with regard to disease symptoms
The available evidence for the effects of the various treatments for RLS on quality of life and sleep outcomes
The available evidence for the harms of the various treatments for RLS
The possibility that the patient might develop augmentation if he/she is taking levodopa or dopamine agonists
Ask the patient at each visit if he/she is experiencing symptoms of augmentation.
Reference
Wilt TJ, MacDonald R, Ouellette J, et al. Treatment for Restless Legs Syndrome. Evidence Report No. 86 (Prepared by the Minnesota Evidence-based Practice Center under Contract No I). AHRQ Publication No. 12(13)-EHC147-EF. Rockville, MD: Agency for Healthcare Research and Quality; November Available at
Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86.
Available at